Vitamin C

cross_nutrient

false

evidence_location

Primary abstract H3K36me2/3 result

experimental_model

Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result

exposure

Vitamin C-supplemented cell culture; exact preparation, dose and duration not recovered from accessible primary abstract.

limitations

No direct claim that Kdm2a/b remove H3K36me3; the combined cellular mark change may involve other enzymes. Abstract-only exposure resolution.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Vitamin C changed methyl marks on histone proteins in cultured mouse fibroblasts.

primary_references

[c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005

tissue_or_cell_type

Embryonic fibroblasts

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1089–1101

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result · source_derived_draft · unverified_draft

### c-reg-h3k36-mark-reduction Vitamin C treatment reduced H3K36me2/3 in mouse embryonic fibroblasts during culture and reprogramming, linking the intervention to histone methylation changes. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C changed methyl marks on histone proteins in cultured mouse fibroblasts. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result limitations: No direct claim that Kdm2a/b remove H3K36me3; the combined cellular mark change may involve other enzymes. Abstract-only exposure resolution. exposure: Vitamin C-supplemented cell culture; exact preparation, dose and duration not recovered from accessible primary abstract. cross_nutrient: false evidence_location: Primary abstract H3K36me2/3 result [c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Clinical boundary for the copper/ascorbate-dependent dopamine beta-hydroxylase pathway.

experimental_model

Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion.

exposure

Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine.

limitations

Plasma catecholamines do not measure all neuronal stores or DBH flux; limited power in five participants.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

An enzyme’s vitamin C requirement did not translate into complete failure of the human stress-signal system.

primary_references

[c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1541–1552

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. · source_derived_draft · unverified_draft

### c-scurvy-catecholamine-reflex-boundary Resting plasma catecholamines and hemodynamic measurements did not change significantly after correction; reflex tachycardia and bradycardia were similar in the deficient and repleted studies. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme’s vitamin C requirement did not translate into complete failure of the human stress-signal system. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. limitations: Plasma catecholamines do not measure all neuronal stores or DBH flux; limited power in five participants. exposure: Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine. cross_nutrient: Clinical boundary for the copper/ascorbate-dependent dopamine beta-hydroxylase pathway. [c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.

exposure

Diet devoid of vitamin C but adequate in other essential nutrients.

limitations

Blood and urine findings are not measurements of every tissue pool.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Very low readings accompanied scurvy, but the historical assay became unreliable near depletion.

primary_references

[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1505–1515

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft

### c-scurvy-circulating-depletion The publisher summary reports near disappearance of ascorbic acid from blood and urine, with erratic low-level readings attributed to an interfering substance. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Very low readings accompanied scurvy, but the historical assay became unreliable near depletion. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: Blood and urine findings are not measurements of every tissue pool. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.

exposure

Diet devoid of vitamin C but adequate in other essential nutrients.

limitations

The human study measured signs, not the contribution of each specific collagen enzyme.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Severe shortage became visible in skin, gums and small-vessel bleeding.

primary_references

[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1493–1503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft

### c-scurvy-mucocutaneous-signs The four completers developed scurvy; recorded signs included follicular hyperkeratosis, swollen bleeding gums and perifollicular or conjunctival hemorrhage. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe shortage became visible in skin, gums and small-vessel bleeding. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: The human study measured signs, not the contribution of each specific collagen enzyme. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion.

exposure

Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine.

limitations

Does not isolate endothelial, smooth-muscle or collagen mechanisms.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

The blood vessels responded less strongly to some constricting signals during shortage.

primary_references

[c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1529–1539

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. · source_derived_draft · unverified_draft

### c-scurvy-vascular-responsiveness Forearm vasoconstriction to intra-arterial norepinephrine and tyramine was greater after repletion; four subjects also had lower resistance-vessel responsiveness to lower-body negative pressure during deficiency. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The blood vessels responded less strongly to some constricting signals during shortage. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. limitations: Does not isolate endothelial, smooth-muscle or collagen mechanisms. exposure: Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine. [c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.

exposure

Diet devoid of vitamin C but adequate in other essential nutrients.

limitations

Wound closure rate is not scar breaking strength; the inspected summary does not establish preserved collagen quality or contradict all wound-healing studies.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Not every commonly expected scurvy endpoint changed in this particular experiment.

primary_references

[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1517–1527

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft

### c-scurvy-wound-rate-boundary Despite the clinical scurvy signs, the report found no abnormality in the measured wound-healing rate, blood counts or coagulation tests. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Not every commonly expected scurvy endpoint changed in this particular experiment. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: Wound closure rate is not scar breaking strength; the inspected summary does not establish preserved collagen quality or contradict all wound-healing studies. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Guinea-pig dietary deficiency with pair feeding and precursor loading

exposure

Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.

limitations

Authors favored excessive excretion as an explanation for depletion; this does not isolate a renal transporter or quantify its contribution in human deficiency.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Greater loss in urine can contribute to low carnitine during vitamin C deficiency.

primary_references

[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

tissue_or_cell_type

Whole animal; urine-based synthesis estimate

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 780–791

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft

### vc-enzyme-deficient-carnitine-excretion Without carnitine-precursor supplements, vitamin-C-deficient guinea pigs excreted approximately three times as much free and total carnitine as replete animals on days 19–28; pair feeding alone did not produce that pattern. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Greater loss in urine can contribute to low carnitine during vitamin C deficiency. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Authors favored excessive excretion as an explanation for depletion; this does not isolate a renal transporter or quantify its contribution in human deficiency. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Guinea-pig vitamin C deficiency and pair-fed comparison

exposure

Vitamin C deficient, control and underfed pair-fed groups; duration not verified in abstract.

limitations

Do not infer that every between-group comparison was statistically significant from these means; biosynthesis was not directly measured.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Both vitamin C shortage and reduced food intake affected liver carnitine in this experiment.

primary_references

[carnitine1983] Combined effect of ascorbic acid deficiency and underfeeding on the hepatic carnitine level in guinea-pigs. (1983). https://pubmed.ncbi.nlm.nih.gov/6852178/ DOI: 10.1007/bf01965181

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 741–752

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig vitamin C deficiency and pair-fed comparison · source_derived_draft · unverified_draft

### vc-enzyme-deficient-liver-carnitine Hepatic carnitine was 148 +/- 9.8 nmol/g in vitamin-C-deficient guinea pigs versus 249 +/- 16.1 in controls; pair-fed animals measured 181 +/- 14.1 nmol/g (means +/- SEM). Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both vitamin C shortage and reduced food intake affected liver carnitine in this experiment. organism: Cavia porcellus tissue_or_cell_type: Liver experimental_model: Guinea-pig vitamin C deficiency and pair-fed comparison limitations: Do not infer that every between-group comparison was statistically significant from these means; biosynthesis was not directly measured. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient, control and underfed pair-fed groups; duration not verified in abstract. [carnitine1983] Combined effect of ascorbic acid deficiency and underfeeding on the hepatic carnitine level in guinea-pigs. (1983). https://pubmed.ncbi.nlm.nih.gov/6852178/ DOI: 10.1007/bf01965181

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Guinea pigs with graded dietary vitamin C supply

exposure

Dietary regimens produced tissue vitamin C approximately 12% versus 100% saturation; regimen duration/dose not verified in abstract.

limitations

No direct synthesis-rate measurement; suggested explanation for human fatigue was not tested.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Low vitamin C coincided with lower muscle carnitine before obvious scurvy signs in these animals.

primary_references

[carnitine1980] Dietary ascorbic acid and muscle carnitine (beta-OH-gamma-(trimethylamino) butyric acid) in guinea-pigs. (1980). https://pubmed.ncbi.nlm.nih.gov/7378344/ DOI: 10.1079/bjn19800102

tissue_or_cell_type

Skeletal muscle

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 728–739

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea pigs with graded dietary vitamin C supply · source_derived_draft · unverified_draft

### vc-enzyme-low-c-muscle-carnitine Guinea pigs with tissue vitamin C around 12% saturation had significantly lower muscle carnitine than animals near 100% saturation, without the customary overt hypovitaminosis-C signs in this experiment. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low vitamin C coincided with lower muscle carnitine before obvious scurvy signs in these animals. organism: Cavia porcellus tissue_or_cell_type: Skeletal muscle experimental_model: Guinea pigs with graded dietary vitamin C supply limitations: No direct synthesis-rate measurement; suggested explanation for human fatigue was not tested. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Dietary regimens produced tissue vitamin C approximately 12% versus 100% saturation; regimen duration/dose not verified in abstract. [carnitine1980] Dietary ascorbic acid and muscle carnitine (beta-OH-gamma-(trimethylamino) butyric acid) in guinea-pigs. (1980). https://pubmed.ncbi.nlm.nih.gov/7378344/ DOI: 10.1079/bjn19800102

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

exposure

Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

limitations

A higher oxidized fraction does not establish higher absolute DHA concentration.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

A larger fraction of the smaller brain vitamin C pool was oxidized.

primary_references

[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

tissue_or_cell_type

Brain

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 468–479

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft

### vc-transport-diet-brain-dha-fraction Chronically vitamin-C-restricted guinea pigs had a higher brain DHA percentage despite lower total brain vitamin C. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A larger fraction of the smaller brain vitamin C pool was oxidized. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: A higher oxidized fraction does not establish higher absolute DHA concentration. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

exposure

Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

limitations

An oxidative marker does not measure every developmental or neurological outcome.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Low vitamin C increased a marker of brain lipid oxidation.

primary_references

[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

tissue_or_cell_type

Brain

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 494–505

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft

### vc-transport-diet-brain-mda Chronically vitamin-C-restricted guinea pigs had higher brain malondialdehyde than vitamin-C-sufficient controls at day 70. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low vitamin C increased a marker of brain lipid oxidation. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: An oxidative marker does not measure every developmental or neurological outcome. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

exposure

Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

limitations

No detected expression difference is not proof of unchanged transport flux, earlier expression, or every cell subtype.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

The measured brain regions did not compensate by detectably increasing SVCT2 abundance.

primary_references

[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

tissue_or_cell_type

Hippocampus, cerebellum and frontal cortex

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 481–492

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft

### vc-transport-diet-brain-svct2 Dietary vitamin C restriction did not significantly alter SVCT2 mRNA or protein in guinea pig hippocampus, cerebellum or frontal cortex at day 70. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured brain regions did not compensate by detectably increasing SVCT2 abundance. organism: Cavia porcellus tissue_or_cell_type: Hippocampus, cerebellum and frontal cortex experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: No detected expression difference is not proof of unchanged transport flux, earlier expression, or every cell subtype. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

exposure

Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

limitations

Non-scorbutic dietary model; total vitamin C includes reduced and oxidized forms.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Long-term low intake reduced the brain vitamin C pool.

primary_references

[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

tissue_or_cell_type

Brain

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 455–466

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft

### vc-transport-diet-brain-vitc Chronic prenatal and postnatal vitamin C restriction lowered brain total vitamin C in day-70 female guinea pigs. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long-term low intake reduced the brain vitamin C pool. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: Non-scorbutic dietary model; total vitamin C includes reduced and oxidized forms. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/creatine-research/17407807.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35", "start_char": 0, "end_char": 1929, "text_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35"}

experimental_model

Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment

exposure

Intrastriatal guanidinoacetate and in-vitro assays; taurine or combined vitamins E plus C pretreatment

limitations

Acute experimental precursor toxicity is not a human supplement trial or proof that antioxidant treatment corrects GAMT deficiency. Vitamin E and C were combined.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Young rats and rat striatal preparations

plain_language

The study tested two antioxidant vitamins together; it did not establish either vitamin as an effective treatment on its own.

primary_references

[creatine-p17407807] Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+,K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. (2007). https://pubmed.ncbi.nlm.nih.gov/17407807/ DOI: 10.1016/j.bbadis.2007.02.005

tissue_or_cell_type

Striatum

trigger_kind

machinery_impairment Imported condition classification; unverified.

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 789–800

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment · source_derived_draft · unverified_draft

### creatine-vitamins-gaa-ck Combined vitamin E plus C pretreatment prevented guanidinoacetate-associated inhibition of creatine kinase and sodium/potassium ATPase. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The study tested two antioxidant vitamins together; it did not establish either vitamin as an effective treatment on its own. organism: Young rats and rat striatal preparations tissue_or_cell_type: Striatum experimental_model: Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment limitations: Acute experimental precursor toxicity is not a human supplement trial or proof that antioxidant treatment corrects GAMT deficiency. Vitamin E and C were combined. exposure: Intrastriatal guanidinoacetate and in-vitro assays; taurine or combined vitamins E plus C pretreatment evidence_span: {"source_cache": "artifacts/creatine-research/17407807.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35", "start_char": 0, "end_char": 1929, "text_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35"} [creatine-p17407807] Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+,K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. (2007). https://pubmed.ncbi.nlm.nih.gov/17407807/ DOI: 10.1016/j.bbadis.2007.02.005

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/creatine-research/17407807.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35", "start_char": 0, "end_char": 1929, "text_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35"}

experimental_model

Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment

exposure

Intrastriatal guanidinoacetate and in-vitro assays; taurine or combined vitamins E plus C pretreatment

limitations

Acute experimental precursor toxicity is not a human supplement trial or proof that antioxidant treatment corrects GAMT deficiency. Vitamin E and C were combined.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Young rats and rat striatal preparations

plain_language

Oxidative damage markers were altered in this preparation, alongside the enzyme effects.

primary_references

[creatine-p17407807] Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+,K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. (2007). https://pubmed.ncbi.nlm.nih.gov/17407807/ DOI: 10.1016/j.bbadis.2007.02.005

tissue_or_cell_type

Striatum

trigger_kind

machinery_impairment Imported condition classification; unverified.

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 802–813

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment · source_derived_draft · unverified_draft

### creatine-vitamins-gaa-oxidation Combined vitamin E plus C pretreatment prevented the rise in the lipid-peroxidation readout after guanidinoacetate exposure. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Oxidative damage markers were altered in this preparation, alongside the enzyme effects. organism: Young rats and rat striatal preparations tissue_or_cell_type: Striatum experimental_model: Acute guanidinoacetate exposure with biochemical assays and antioxidant pretreatment limitations: Acute experimental precursor toxicity is not a human supplement trial or proof that antioxidant treatment corrects GAMT deficiency. Vitamin E and C were combined. exposure: Intrastriatal guanidinoacetate and in-vitro assays; taurine or combined vitamins E plus C pretreatment evidence_span: {"source_cache": "artifacts/creatine-research/17407807.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35", "start_char": 0, "end_char": 1929, "text_sha256": "6174f6169ebf6ca7e61bc61642e38841a9089aecdd278ad8fb2f2221cf847c35"} [creatine-p17407807] Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+,K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. (2007). https://pubmed.ncbi.nlm.nih.gov/17407807/ DOI: 10.1016/j.bbadis.2007.02.005

evidence_span

{"source_cache": "artifacts/hbot-research/2537773.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe", "start_char": 0, "end_char": 2024, "text_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe"}

experimental_model

Review of prolyl 4-hydroxylase enzymology and subunit structure

exposure

Hydroxylation of proline in X-Pro-Gly sequences

limitations

An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Mammalian enzyme

plain_language

Vitamin C is not used up every turn; it is the reserve that resets the enzyme when a cycle misfires.

primary_references

[hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

tissue_or_cell_type

Endoplasmic reticulum

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 868–879

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of prolyl 4-hydroxylase enzymology and subunit structure · source_derived_draft · unverified_draft

### hbot-ascorbate-uncoupled-cycles Ascorbate is not consumed during most catalytic cycles, but the enzyme also decarboxylates 2-oxoglutarate without subsequent hydroxylation, and ascorbate is required as a specific alternative oxygen acceptor in those uncoupled cycles. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C is not used up every turn; it is the reserve that resets the enzyme when a cycle misfires. organism: Mammalian enzyme tissue_or_cell_type: Endoplasmic reticulum experimental_model: Review of prolyl 4-hydroxylase enzymology and subunit structure limitations: An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis. exposure: Hydroxylation of proline in X-Pro-Gly sequences evidence_span: {"source_cache": "artifacts/hbot-research/2537773.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe", "start_char": 0, "end_char": 2024, "text_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe"} [hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/cold-research/3949732.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1", "start_char": 0, "end_char": 2000, "text_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1"}

experimental_model

Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate

exposure

Tyramine- or dopamine-stimulated turnover with extragranular ascorbate

limitations

An in vitro demonstration in intact granules. Ascorbate itself does not cross the membrane, which is precisely why a shuttle is required.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine

plain_language

Every molecule of noradrenaline made costs the vesicle a molecule of vitamin C.

primary_references

[cold-p3949732] Evidence for an ascorbate shuttle for the transfer of reducing equivalents across chromaffin granule membranes. (1986). https://pubmed.ncbi.nlm.nih.gov/3949732/ DOI: 10.1016/s0021-9258(17)35819-2

tissue_or_cell_type

Adrenal chromaffin granules

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 611–622

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate · source_derived_draft · unverified_draft

### cold-ascorbate-depletion-in-granule Incubation with tyramine produced a time-dependent decrease in reduced intragranular ascorbate proportional to extragranular tyramine concentration over 50 microM to 2 mM. Condition category: nutrient_deficiency nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Every molecule of noradrenaline made costs the vesicle a molecule of vitamin C. organism: Bovine tissue_or_cell_type: Adrenal chromaffin granules experimental_model: Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate limitations: An in vitro demonstration in intact granules. Ascorbate itself does not cross the membrane, which is precisely why a shuttle is required. exposure: Tyramine- or dopamine-stimulated turnover with extragranular ascorbate evidence_span: {"source_cache": "artifacts/cold-research/3949732.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1", "start_char": 0, "end_char": 2000, "text_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1"} [cold-p3949732] Evidence for an ascorbate shuttle for the transfer of reducing equivalents across chromaffin granule membranes. (1986). https://pubmed.ncbi.nlm.nih.gov/3949732/ DOI: 10.1016/s0021-9258(17)35819-2

evidence_span

{"source_cache": "artifacts/cold-research/3676254.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a", "start_char": 0, "end_char": 1648, "text_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a"}

experimental_model

Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants

exposure

Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects

limitations

A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine enzyme

plain_language

Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls.

primary_references

[cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

tissue_or_cell_type

Purified enzyme

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 585–596

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants · source_derived_draft · unverified_draft

### cold-ascorbate-reductant Ascorbate is the presumed in vivo reductant of dopamine beta-monooxygenase; the one-electron reductant ferrocyanide was nearly as kinetically competent, while dopamine as sole reductant reduced enzymic copper in a rate-limiting step 40-fold slower than with ascorbate, and the reductant binds at a site physically distinct from the substrate site. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls. organism: Bovine enzyme tissue_or_cell_type: Purified enzyme experimental_model: Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants limitations: A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling. exposure: Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects evidence_span: {"source_cache": "artifacts/cold-research/3676254.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a", "start_char": 0, "end_char": 1648, "text_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a"} [cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

cross_nutrient

true

evidence_location

Figure 6C

experimental_model

Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue

exposure

15 pmol ascorbate/cell (approximately 8 mM), 1 h; catalase rescue 50-MOI vector transduction 36 h before treatment.

limitations

Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. Total assay does not resolve cytosolic ACO1 from mitochondrial ACO2.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

High-concentration vitamin C impaired an iron-sulfur enzyme in these cancer cells, and removing peroxide protected its activity.

primary_references

[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

tissue_or_cell_type

NSCLC cell cultures

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1327–1339

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue · source_derived_draft · unverified_draft

### c-reg-aconitase-inactivation Pharmacological ascorbate decreased total cellular aconitase activity in NSCLC cultures; catalase overexpression prevented this activity loss, implicating peroxide-dependent injury to the Fe-S enzyme system. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: High-concentration vitamin C impaired an iron-sulfur enzyme in these cancer cells, and removing peroxide protected its activity. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. Total assay does not resolve cytosolic ACO1 from mitochondrial ACO2. exposure: 15 pmol ascorbate/cell (approximately 8 mM), 1 h; catalase rescue 50-MOI vector transduction 36 h before treatment. cross_nutrient: true evidence_location: Figure 6C [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

cross_nutrient

false

evidence_location

Figure 3A

experimental_model

Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h

exposure

Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Catalase 100 µg/mL preincubated 30 min.

limitations

Primary paper identifies catalase but does not specify species in the inspected Methods; the source species should not be inferred. Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens cells; experimental catalase preparation

plain_language

Breaking down peroxide outside the cells prevented the vitamin C-associated killing.

primary_references

[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

tissue_or_cell_type

Burkitt lymphoma cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1243–1255

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h · source_derived_draft · unverified_draft

### c-reg-catalase-protects-lymphoma Extracellular catalase prevented JLP-119 cell death after 2 mM ascorbate, supporting peroxide as a required mediator in this culture experiment. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Breaking down peroxide outside the cells prevented the vitamin C-associated killing. organism: Homo sapiens cells; experimental catalase preparation tissue_or_cell_type: Burkitt lymphoma cells experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h limitations: Primary paper identifies catalase but does not specify species in the inspected Methods; the source species should not be inferred. Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Catalase 100 µg/mL preincubated 30 min. cross_nutrient: false evidence_location: Figure 3A [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

cross_nutrient

true

evidence_location

Figure 6D

experimental_model

Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays

exposure

15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays.

limitations

Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

This high-concentration exposure impaired respiratory complex I in the studied cancer cells.

primary_references

[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

tissue_or_cell_type

NSCLC cell cultures

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1341–1353

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays · source_derived_draft · unverified_draft

### c-reg-complex-i-inactivation After 15 pmol/cell (approximately 8 mM) ascorbate for 1 h, NSCLC lysates showed reduced respiratory-complex I activity while the separately assayed complex IV activity was retained, consistent with vulnerability of Fe-S-containing machinery. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This high-concentration exposure impaired respiratory complex I in the studied cancer cells. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed. exposure: 15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays. cross_nutrient: true evidence_location: Figure 6D [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

cross_nutrient

true

evidence_location

Figure 6D

experimental_model

Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays

exposure

15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays.

limitations

Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

The exposure also impaired respiratory complex II, which participates in respiration and the citric acid cycle.

primary_references

[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

tissue_or_cell_type

NSCLC cell cultures

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1383–1395

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays · source_derived_draft · unverified_draft

### c-reg-complex-ii-inactivation The same pharmacological ascorbate exposure reduced NSCLC respiratory-complex II activity, extending the observed impairment to a second Fe-S-containing respiratory complex; complex IV activity was retained. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The exposure also impaired respiratory complex II, which participates in respiration and the citric acid cycle. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed. exposure: 15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays. cross_nutrient: true evidence_location: Figure 6D [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

cross_nutrient

false

evidence_location

Figure 5C; Methods RBC mixtures

experimental_model

Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells

exposure

Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Reconstituted 25% or 50% hematocrit; lymphoma cells recovered before later assessment.

limitations

Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Protective blood-cell mixture is not proof that all extravascular compartments are equally protected.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Red blood cells removed the damaging chemistry sufficiently to protect the lymphoma cells in this mixture.

primary_references

[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

tissue_or_cell_type

Lymphoma/erythrocyte coculture

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1271–1283

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells · source_derived_draft · unverified_draft

### c-reg-erythrocytes-protect-lymphoma Adding human erythrocytes at 25% or 50% hematocrit protected JLP-119 lymphoma cells from the 2 mM ascorbate challenge, demonstrating that blood-cell clearance can change an otherwise cytotoxic culture exposure. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Red blood cells removed the damaging chemistry sufficiently to protect the lymphoma cells in this mixture. organism: Homo sapiens tissue_or_cell_type: Lymphoma/erythrocyte coculture experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Protective blood-cell mixture is not proof that all extravascular compartments are equally protected. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Reconstituted 25% or 50% hematocrit; lymphoma cells recovered before later assessment. cross_nutrient: false evidence_location: Figure 5C; Methods RBC mixtures [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

cross_nutrient

false

evidence_location

Figures 1–2

experimental_model

Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation

exposure

100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.

limitations

5hmC abundance alone is not proof of completed demethylation; cultured ESCs are not adult human tissues.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

A stable vitamin C derivative increased an early DNA-demethylation intermediate in cultured mouse stem cells.

primary_references

[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

tissue_or_cell_type

Embryonic stem cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 977–989

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation · source_derived_draft · unverified_draft

### c-reg-esc-hydroxymethylation Adding L-ascorbic acid 2-phosphate to mouse ESC medium rapidly increased global DNA 5hmC and promoter-associated 5hmC, preceding later methylcytosine loss. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A stable vitamin C derivative increased an early DNA-demethylation intermediate in cultured mouse stem cells. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation limitations: 5hmC abundance alone is not proof of completed demethylation; cultured ESCs are not adult human tissues. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figures 1–2 [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

cross_nutrient

false

evidence_location

Figure 2; resistant-region analysis

experimental_model

Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation

exposure

100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.

limitations

Locus-selective cell-culture result; promoter demethylation did not automatically activate every affected gene.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Vitamin C changed selected DNA methylation patterns in these cells; protected regions retained their marks.

primary_references

[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

tissue_or_cell_type

Embryonic stem cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 991–1003

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation · source_derived_draft · unverified_draft

### c-reg-esc-promoter-demethylation After vitamin C derivative treatment, numerous mouse ESC promoters lost methylcytosine; imprinted regions and IAP retroelements were relatively resistant, so the effect was not indiscriminate erasure of genomic methylation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C changed selected DNA methylation patterns in these cells; protected regions retained their marks. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation limitations: Locus-selective cell-culture result; promoter demethylation did not automatically activate every affected gene. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figure 2; resistant-region analysis [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

cross_nutrient

true

evidence_location

Figure 1a–b; treatment Methods

experimental_model

Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays

exposure

5 or 10 mM freshly neutralized ascorbic acid, 2 h, then wash/recovery; FAC adds 5–30 µM iron to medium containing 5.6 ±1.3 µM total iron.

limitations

FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

In this medium, extra iron protected the prostate cancer cells from high-concentration vitamin C.

primary_references

[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

tissue_or_cell_type

Prostate carcinoma cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1285–1297

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays · source_derived_draft · unverified_draft

### c-reg-extracellular-iron-cytoprotection Supplementing RPMI/FCS with as little as 5 µM iron as FAC prevented the marked viability loss caused by 5–10 mM ascorbate in LNCaP and PC-3 cultures; protection also occurred at higher tested iron additions. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this medium, extra iron protected the prostate cancer cells from high-concentration vitamin C. organism: Homo sapiens tissue_or_cell_type: Prostate carcinoma cells experimental_model: Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays limitations: FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. exposure: 5 or 10 mM freshly neutralized ascorbic acid, 2 h, then wash/recovery; FAC adds 5–30 µM iron to medium containing 5.6 ±1.3 µM total iron. cross_nutrient: true evidence_location: Figure 1a–b; treatment Methods [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

cross_nutrient

true

evidence_location

Figure 2a–b; Oximetry Methods

experimental_model

Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release

exposure

5 mM ascorbate ±5 µM FAC iron; oxygen trace and 600 U catalase addition after about 15 min.

limitations

FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. The endpoint measures net peroxide and does not separately determine every elementary redox rate.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cell-free bovine-serum-containing medium

plain_language

Iron sped up vitamin C oxidation while also helping remove the peroxide produced.

primary_references

[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

tissue_or_cell_type

RPMI-1640 +10% FCS

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1299–1311

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release · source_derived_draft · unverified_draft

### c-reg-extracellular-iron-peroxide-removal In RPMI/FCS exposed to 5 mM ascorbate, added 5 µM FAC iron accelerated oxygen consumption/ascorbate oxidation but reduced detectable peroxide accumulation, showing that faster oxidation need not yield a larger steady peroxide pool. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron sped up vitamin C oxidation while also helping remove the peroxide produced. organism: Cell-free bovine-serum-containing medium tissue_or_cell_type: RPMI-1640 +10% FCS experimental_model: Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release limitations: FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. The endpoint measures net peroxide and does not separately determine every elementary redox rate. exposure: 5 mM ascorbate ±5 µM FAC iron; oxygen trace and 600 U catalase addition after about 15 min. cross_nutrient: true evidence_location: Figure 2a–b; Oximetry Methods [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

cross_nutrient

true

evidence_location

Figure 3a–c; Results discussing failed EPR spin trapping

experimental_model

Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay

exposure

5 mM ascorbate ±5 µM FAC iron for 2 h in RPMI-1640 +10% FCS; additional 30 µM iron experiment gave similar results. Thiols assayed using 100 µM RSSR probe.

limitations

Observed protein oxidation supports but does not directly prove the proposed hydroxyl-radical buffering mechanism. FAC speciation and medium composition limit tissue extrapolation.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens LNCaP/PC-3 cells; bovine-serum-containing extracellular medium

plain_language

Extra iron shifted more oxidation onto proteins in the culture liquid while protecting the cells. The proposed short-lived radical intermediate could not be directly measured.

primary_references

[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

tissue_or_cell_type

Prostate cancer-cell cultures and their extracellular RPMI/FCS medium

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1313–1325

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay · source_derived_draft · unverified_draft

### c-reg-extracellular-protein-oxidation Adding iron to pharmacological ascorbate increased measured extracellular protein oxidation about threefold in the RPMI/FCS experiment while preserving intracellular thiols. The authors interpreted this as extracellular interception of Fenton-derived oxidants; direct hydroxyl-radical spin trapping was unsuccessful because ascorbate reduced the spin adducts. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra iron shifted more oxidation onto proteins in the culture liquid while protecting the cells. The proposed short-lived radical intermediate could not be directly measured. organism: Homo sapiens LNCaP/PC-3 cells; bovine-serum-containing extracellular medium tissue_or_cell_type: Prostate cancer-cell cultures and their extracellular RPMI/FCS medium experimental_model: Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay limitations: Observed protein oxidation supports but does not directly prove the proposed hydroxyl-radical buffering mechanism. FAC speciation and medium composition limit tissue extrapolation. exposure: 5 mM ascorbate ±5 µM FAC iron for 2 h in RPMI-1640 +10% FCS; additional 30 µM iron experiment gave similar results. Thiols assayed using 100 µM RSSR probe. cross_nutrient: true evidence_location: Figure 3a–c; Results discussing failed EPR spin trapping [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955

cross_nutrient

true

evidence_location

Figure 6I–L

experimental_model

H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays

exposure

20-MOI ferritin-heavy-chain expression 36 h before experiment; 5 pmol/cell (approximately 2–3 mM) ascorbate for 1 h.

limitations

Engineered overexpression is not dietary iron deficiency or ordinary ferritin concentration; serum ferritin does not measure this intracellular intervention.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Locking more iron into ferritin protected these lung cancer cells from the exposure.

primary_references

[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

tissue_or_cell_type

NSCLC cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1369–1381

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays · source_derived_draft · unverified_draft

### c-reg-ferritin-heavy-protects Ferritin-heavy-chain overexpression in H1299 cells lowered labile iron and increased clonogenic survival after pharmacological ascorbate, supporting a protective role of intracellular iron sequestration in this setting. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Locking more iron into ferritin protected these lung cancer cells from the exposure. organism: Homo sapiens tissue_or_cell_type: NSCLC cells experimental_model: H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays limitations: Engineered overexpression is not dietary iron deficiency or ordinary ferritin concentration; serum ferritin does not measure this intracellular intervention. exposure: 20-MOI ferritin-heavy-chain expression 36 h before experiment; 5 pmol/cell (approximately 2–3 mM) ascorbate for 1 h. cross_nutrient: true evidence_location: Figure 6I–L [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

cross_nutrient

true

evidence_location

Primary abstract rate/extent and substrate comparisons

experimental_model

Purified enzyme with human HIF-1 alpha-derived peptide substrate

exposure

Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract.

limitations

Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Human HIF-1 alpha substrate; purified recombinant hydroxylase

plain_language

Vitamin C also supported a different HIF enzyme that modifies an asparagine site.

primary_references

[c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1131–1143

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified enzyme with human HIF-1 alpha-derived peptide substrate · source_derived_draft · unverified_draft

### c-reg-fih-ascorbate Ascorbate increased the initial rate and extent of FIH-catalyzed asparaginyl hydroxylation of human HIF-1 alpha peptide; the study separately tested a consensus ankyrin-repeat peptide. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C also supported a different HIF enzyme that modifies an asparagine site. organism: Human HIF-1 alpha substrate; purified recombinant hydroxylase tissue_or_cell_type: Cell-free experimental_model: Purified enzyme with human HIF-1 alpha-derived peptide substrate limitations: Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF. exposure: Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract. cross_nutrient: true evidence_location: Primary abstract rate/extent and substrate comparisons [c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609

cross_nutrient

true

evidence_location

Figure 2A–B; hydroxylation Methods

experimental_model

Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding

exposure

10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM.

limitations

Alternative reductant effects vary with substrate and assay; this is not a nutritional substitution recommendation or proof of in-vivo compensation mechanism.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens proteins

plain_language

These oxygen-sensing enzymes could use support from glutathione when vitamin C was absent in the test tube.

primary_references

[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1145–1157

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding · source_derived_draft · unverified_draft

### c-reg-gsh-substitutes-phd Reduced glutathione stimulated all three tested PHD isoforms in the absence of ascorbate; millimolar GSH could substitute in the peptide assay, indicating reductant redundancy in this setting. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: These oxygen-sensing enzymes could use support from glutathione when vitamin C was absent in the test tube. organism: Homo sapiens proteins tissue_or_cell_type: Cell-free experimental_model: Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding limitations: Alternative reductant effects vary with substrate and assay; this is not a nutritional substitution recommendation or proof of in-vivo compensation mechanism. exposure: 10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. cross_nutrient: true evidence_location: Figure 2A–B; hydroxylation Methods [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Figure 5C–D; Animal studies

experimental_model

Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls

exposure

Maintenance 0.33 g/L ascorbic acid drinking water; withdrawal about 35–36 days; 8% inspired oxygen for 24 h.

limitations

Dietary deficiency in a synthesis-null animal; does not establish that every HIF target or tissue is unaffected, nor a safe human deficiency threshold.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Even severely vitamin-C-depleted mice retained this measured hormonal response to low oxygen.

primary_references

[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

tissue_or_cell_type

Plasma erythropoietin; kidney Epo mRNA supporting endpoint

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1187–1199

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls · source_derived_draft · unverified_draft

### c-reg-gulo-depletion-epo-preserved Male Gulo-null mice deprived of vitamin C for approximately five weeks retained a robust plasma erythropoietin response to 24 h at 8% oxygen, similar to supplemented controls, despite plasma ascorbate at or below 1 µM and scorbutic weight loss. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even severely vitamin-C-depleted mice retained this measured hormonal response to low oxygen. organism: Mus musculus tissue_or_cell_type: Plasma erythropoietin; kidney Epo mRNA supporting endpoint experimental_model: Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls limitations: Dietary deficiency in a synthesis-null animal; does not establish that every HIF target or tissue is unaffected, nor a safe human deficiency threshold. exposure: Maintenance 0.33 g/L ascorbic acid drinking water; withdrawal about 35–36 days; 8% inspired oxygen for 24 h. cross_nutrient: false evidence_location: Figure 5C–D; Animal studies [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Figure 1B–C

experimental_model

HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter

exposure

0 versus 50 µM ascorbate; 0.2% versus 21% oxygen for 6-h protein assay, graded oxygen for 24-h reporter assay.

limitations

Cell-culture omission, not a controlled human dietary deficiency; residual adaptive reductant pathways were not eliminated.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Removing vitamin C from this adapted cancer-cell culture did not switch off its measured low-oxygen response.

primary_references

[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

tissue_or_cell_type

Cervical carcinoma cells

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1173–1185

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter · source_derived_draft · unverified_draft

### c-reg-hela-hypoxia-preserved HeLa cells maintained in serum-free, ascorbate-free defined medium retained hypoxic HIF-1 alpha stabilization and HIF-dependent reporter activation relative to cells supplied with 50 µM ascorbate. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing vitamin C from this adapted cancer-cell culture did not switch off its measured low-oxygen response. organism: Homo sapiens tissue_or_cell_type: Cervical carcinoma cells experimental_model: HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter limitations: Cell-culture omission, not a controlled human dietary deficiency; residual adaptive reductant pathways were not eliminated. exposure: 0 versus 50 µM ascorbate; 0.2% versus 21% oxygen for 6-h protein assay, graded oxygen for 24-h reporter assay. cross_nutrient: false evidence_location: Figure 1B–C [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Primary abstract gain/loss-of-function result

experimental_model

Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function

exposure

Genetic gain/loss interventions during vitamin C-supported reprogramming; exact construct, dose and timing not recovered.

limitations

Abstract-level mechanistic assignment; no quantitative effect size or specific knockdown efficiency asserted.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

The histone enzymes were part of the machinery through which vitamin C helped cells reprogram.

primary_references

[c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005

tissue_or_cell_type

Embryonic fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1103–1115

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function · source_derived_draft · unverified_draft

### c-reg-jhdm-reprogramming-effectors Jhdm1a/1b gain- and loss-of-function experiments identified these histone demethylases as functional effectors of vitamin-C-enhanced mouse somatic-cell reprogramming. Loss-of-function reduced the response rather than being corrected by vitamin C alone. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The histone enzymes were part of the machinery through which vitamin C helped cells reprogram. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function limitations: Abstract-level mechanistic assignment; no quantitative effect size or specific knockdown efficiency asserted. exposure: Genetic gain/loss interventions during vitamin C-supported reprogramming; exact construct, dose and timing not recovered. cross_nutrient: false evidence_location: Primary abstract gain/loss-of-function result [c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005

cross_nutrient

false

evidence_location

Figure 2D–E

experimental_model

Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h

exposure

Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium.

limitations

Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. This conclusion is specific to this line and loading protocol.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

The killing depended on vitamin C outside these lymphoma cells, not merely on having vitamin C inside them.

primary_references

[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

tissue_or_cell_type

Burkitt lymphoma cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1229–1241

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h · source_derived_draft · unverified_draft

### c-reg-lymphoma-extracellular-ascorbate JLP-119 lymphoma cells died after extracellular ascorbate exposure even when previously loaded to about 3 mM intracellular ascorbate; matched loading through dehydroascorbic acid did not reproduce the extracellular-ascorbate death effect. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The killing depended on vitamin C outside these lymphoma cells, not merely on having vitamin C inside them. organism: Homo sapiens tissue_or_cell_type: Burkitt lymphoma cells experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. This conclusion is specific to this line and loading protocol. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. cross_nutrient: false evidence_location: Figure 2D–E [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

cross_nutrient

false

evidence_location

Figure 4A–C

experimental_model

Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR

exposure

0.2–2 mM ascorbate over 1 h; 2 mM ascorbate with 0.5–10% FBS in serum-dependence experiment.

limitations

Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Net accumulation reflects both production and removal; ascorbate can interfere with routine peroxidase assays.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cell-free; bovine serum-containing medium

plain_language

The culture liquid itself could turn high-concentration vitamin C into peroxide.

primary_references

[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

tissue_or_cell_type

Extracellular assay medium

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1257–1269

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR · source_derived_draft · unverified_draft

### c-reg-medium-peroxide-generation Ascorbate produced peroxide in cell culture medium without requiring cells; accumulation depended on ascorbate concentration, time and serum fraction, and tracked ascorbyl radical detected by EPR. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The culture liquid itself could turn high-concentration vitamin C into peroxide. organism: Cell-free; bovine serum-containing medium tissue_or_cell_type: Extracellular assay medium experimental_model: Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Net accumulation reflects both production and removal; ascorbate can interfere with routine peroxidase assays. exposure: 0.2–2 mM ascorbate over 1 h; 2 mM ascorbate with 0.5–10% FBS in serum-dependence experiment. cross_nutrient: false evidence_location: Figure 4A–C [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102

cross_nutrient

true

evidence_location

Figure 2C

experimental_model

Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate

exposure

10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. Ascorbate measured before and after 1 h.

limitations

Minor air oxidation remained possible; result does not exclude ascorbate consumption during uncoupled or oxidative-damage reactions.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens protein

plain_language

Vitamin C was not used up once for every hydroxylation event in this enzyme assay.

primary_references

[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1159–1171

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate · source_derived_draft · unverified_draft

### c-reg-phd-ascorbate-not-stoichiometric HPLC showed only a small decline in ascorbate during the PHD2 peptide reaction, independent of hydroxyl-acceptor substrate, providing no evidence that coupled prolyl hydroxylation consumed ascorbate stoichiometrically. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C was not used up once for every hydroxylation event in this enzyme assay. organism: Homo sapiens protein tissue_or_cell_type: Cell-free experimental_model: Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate limitations: Minor air oxidation remained possible; result does not exclude ascorbate consumption during uncoupled or oxidative-damage reactions. exposure: 10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. Ascorbate measured before and after 1 h. cross_nutrient: true evidence_location: Figure 2C [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637

cross_nutrient

true

evidence_location

Primary abstract rate/extent and substrate comparisons

experimental_model

Purified enzyme with human HIF-1 alpha-derived peptide substrate

exposure

Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract.

limitations

Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Human HIF-1 alpha substrate; purified recombinant hydroxylase

plain_language

Vitamin C increased the activity of an isolated oxygen-sensing proline hydroxylase.

primary_references

[c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1117–1129

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified enzyme with human HIF-1 alpha-derived peptide substrate · source_derived_draft · unverified_draft

### c-reg-phd2-ascorbate Ascorbate increased the initial rate and extent of PHD2-catalyzed hydroxylation at both tested human HIF-1 alpha prolyl sites in purified-enzyme peptide experiments. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C increased the activity of an isolated oxygen-sensing proline hydroxylase. organism: Human HIF-1 alpha substrate; purified recombinant hydroxylase tissue_or_cell_type: Cell-free experimental_model: Purified enzyme with human HIF-1 alpha-derived peptide substrate limitations: Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF. exposure: Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract. cross_nutrient: true evidence_location: Primary abstract rate/extent and substrate comparisons [c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609

cross_nutrient

true

evidence_location

Figure 4A–C

experimental_model

KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts

exposure

50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol.

limitations

Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better.

primary_references

[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

tissue_or_cell_type

Epiblast stem-cell culture

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1075–1087

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts · source_derived_draft · unverified_draft

### c-reg-retinol-ascorbate-reprogramming Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better. organism: Mus musculus tissue_or_cell_type: Epiblast stem-cell culture experimental_model: KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts limitations: Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof. exposure: 50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol. cross_nutrient: true evidence_location: Figure 4A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

cross_nutrient

true

evidence_location

Figure 3A–C

experimental_model

Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification

exposure

Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays.

limitations

Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect.

primary_references

[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

tissue_or_cell_type

Naïve embryonic stem cells

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1047–1059

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification · source_derived_draft · unverified_draft

### c-reg-retinol-tet2-expression Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification limitations: Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues. exposure: Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays. cross_nutrient: true evidence_location: Figure 3A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Figure 5C–E

experimental_model

SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival

exposure

10 pmol/cell (2 mM) ascorbate for 1 h; LIP measured with 500 nM calcein-AM and 100 µM 2,2′-bipyridyl dequenching.

limitations

SOD2 genotype is not dietary manganese deficiency; DHE oxidation alone is not chemically specific proof of superoxide. Study does not identify a universal cancer-selectivity mechanism.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens

plain_language

Removing a mitochondrial antioxidant enzyme made these lung cancer cells more vulnerable to the high-dose exposure.

primary_references

[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

tissue_or_cell_type

Lung adenocarcinoma cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1355–1367

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival · source_derived_draft · unverified_draft

### c-reg-sod2-loss-sensitizes SOD2 knockout A549 cells had higher basal labile iron and greater clonogenic killing by ascorbate than parental cells, linking antioxidant machinery impairment to sensitivity in this model. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing a mitochondrial antioxidant enzyme made these lung cancer cells more vulnerable to the high-dose exposure. organism: Homo sapiens tissue_or_cell_type: Lung adenocarcinoma cells experimental_model: SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival limitations: SOD2 genotype is not dietary manganese deficiency; DHE oxidation alone is not chemically specific proof of superoxide. Study does not identify a universal cancer-selectivity mechanism. exposure: 10 pmol/cell (2 mM) ascorbate for 1 h; LIP measured with 500 nM calcein-AM and 100 µM 2,2′-bipyridyl dequenching. cross_nutrient: true evidence_location: Figure 5C–E [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Figure 3b–c

experimental_model

Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR

exposure

100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.

limitations

Genetic loss of machinery, not low vitamin intake; other vitamin C effects and residual Tet3 were not excluded.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

Vitamin C could not restore these DNA effects when the two relevant enzymes were genetically absent.

primary_references

[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

tissue_or_cell_type

Embryonic stem cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1005–1017

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR · source_derived_draft · unverified_draft

### c-reg-tet-dko-blocks-response Combined Tet1/Tet2 deletion in mouse ESCs abolished the vitamin-C-induced increase in 5hmC and promoter demethylation observed in wild-type cells; residual antibody signal was not interpreted as robust Tet activity. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C could not restore these DNA effects when the two relevant enzymes were genetically absent. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR limitations: Genetic loss of machinery, not low vitamin intake; other vitamin C effects and residual Tet3 were not excluded. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figure 3b–c [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

cross_nutrient

true

evidence_location

Figure 1D–E; Figure S1A–C

experimental_model

Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay

exposure

1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0.

limitations

This does not directly measure free iron inside cells or establish a dietary iron/ascorbate requirement.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus protein expressed in Escherichia coli

plain_language

Vitamin C helped restore the usable iron needed by this isolated DNA-modifying enzyme.

primary_references

[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1019–1031

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay · source_derived_draft · unverified_draft

### c-reg-tet-iron-reduction-rescue Ascorbate restored murine TET1-CD activity with ferric iron or under pH 8.0 conditions that rapidly oxidized Fe(II); iron-redox measurements support provision of reduced iron as the rescue mechanism. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped restore the usable iron needed by this isolated DNA-modifying enzyme. organism: Mus musculus protein expressed in Escherichia coli tissue_or_cell_type: Cell-free experimental_model: Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay limitations: This does not directly measure free iron inside cells or establish a dietary iron/ascorbate requirement. exposure: 1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. cross_nutrient: true evidence_location: Figure 1D–E; Figure S1A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

cross_nutrient

true

evidence_location

Figure 1D; Figure S1B–D

experimental_model

Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay

exposure

1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. Substrate-free preincubation up to 30 min.

limitations

A conditional biochemical null result; it does not negate ascorbate enhancement in cells or more oxidizing buffers.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus protein expressed in Escherichia coli

plain_language

With usable iron maintained in this assay, the enzyme did not require extra vitamin C to keep working.

primary_references

[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1033–1045

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay · source_derived_draft · unverified_draft

### c-reg-tet-sufficient-ferrous-iron At pH 6.8 with sufficient Fe(II), murine TET1-CD remained active without ascorbate and adding ascorbate did not increase the measured activity; substrate-free preincubation also did not rapidly destroy activity. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: With usable iron maintained in this assay, the enzyme did not require extra vitamin C to keep working. organism: Mus musculus protein expressed in Escherichia coli tissue_or_cell_type: Cell-free experimental_model: Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay limitations: A conditional biochemical null result; it does not negate ascorbate enhancement in cells or more oxidizing buffers. exposure: 1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. Substrate-free preincubation up to 30 min. cross_nutrient: true evidence_location: Figure 1D; Figure S1B–D [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

cross_nutrient

true

evidence_location

Figure 3a; Methods Tet activity assay

experimental_model

Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA

exposure

10 min at 37°C; 1.2 µg enzyme, 178.2 ng DNA, 3.7 µM ammonium iron(II) sulfate, 1 mM 2-oxoglutarate, titrated vitamin C (Sigma A5960).

limitations

Purified-domain result; oxidation-prone buffer differs from cellular iron conditions. Exact plotted titration values not transcribed.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Homo sapiens protein

plain_language

Vitamin C helped the isolated human enzyme modify DNA under these test conditions.

primary_references

[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

tissue_or_cell_type

Cell-free

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 963–975

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA · source_derived_draft · unverified_draft

### c-reg-tet1-human-activity Vitamin C increased hydroxymethylcytosine production by recombinant human TET1 catalytic domain in the reported pH 8.0 assay containing Fe(II) and 2-oxoglutarate. This demonstrates assay enhancement, without establishing obligatory ascorbate binding. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped the isolated human enzyme modify DNA under these test conditions. organism: Homo sapiens protein tissue_or_cell_type: Cell-free experimental_model: Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA limitations: Purified-domain result; oxidation-prone buffer differs from cellular iron conditions. Exact plotted titration values not transcribed. exposure: 10 min at 37°C; 1.2 µg enzyme, 178.2 ng DNA, 3.7 µM ammonium iron(II) sulfate, 1 mM 2-oxoglutarate, titrated vitamin C (Sigma A5960). cross_nutrient: true evidence_location: Figure 3a; Methods Tet activity assay [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Figure 3E–F

experimental_model

CRISPR Tet2 ΔRARE naïve ESCs compared with wild type

exposure

Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253.

limitations

Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Mus musculus

plain_language

The vitamin A response depended on a specific DNA control sequence in the Tet2 gene.

primary_references

[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

tissue_or_cell_type

Naïve embryonic stem cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1061–1073

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR Tet2 ΔRARE naïve ESCs compared with wild type · source_derived_draft · unverified_draft

### c-reg-tet2-rare-deletion Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The vitamin A response depended on a specific DNA control sequence in the Tet2 gene. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: CRISPR Tet2 ΔRARE naïve ESCs compared with wild type limitations: Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency. exposure: Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253. cross_nutrient: true evidence_location: Figure 3E–F [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113

cross_nutrient

true

evidence_location

Primary abstract final result

experimental_model

Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements

exposure

Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M.

limitations

This persistence endpoint is separate from the radical-reduction reaction and does not establish a supplementation effect in people.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Glycine max lipid preparation; cell-free

plain_language

Vitamin C prolonged vitamin E’s protection against oxidation in the liposome experiment.

primary_references

[c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9

tissue_or_cell_type

Artificial liposomes

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1215–1227

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements · source_derived_draft · unverified_draft

### c-reg-tocopherol-antiperoxidation-persistence The inhibitory effect of alpha-tocopherol on liposome lipid peroxidation persisted while aqueous ascorbic acid remained available, consistent with continued tocopherol-radical recycling. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C prolonged vitamin E’s protection against oxidation in the liposome experiment. organism: Glycine max lipid preparation; cell-free tissue_or_cell_type: Artificial liposomes experimental_model: Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements limitations: This persistence endpoint is separate from the radical-reduction reaction and does not establish a supplementation effect in people. exposure: Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M. cross_nutrient: true evidence_location: Primary abstract final result [c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9

cross_nutrient

true

evidence_location

Primary abstract radical accessibility and kinetic result

experimental_model

Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements

exposure

Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M.

limitations

Membrane composition, radical initiator and assay conditions determine kinetics; no human clinical benefit or universal membrane rate is established.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Glycine max lipid preparation; cell-free

plain_language

Vitamin C recycled the vitamin E radical back into vitamin E across this artificial membrane-water interface.

primary_references

[c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9

tissue_or_cell_type

Artificial liposomes

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1201–1213

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements · source_derived_draft · unverified_draft

### c-reg-tocopherol-radical-recycling Aqueous ascorbate reduced bilayer alpha-tocopheroxyl radical back to alpha-tocopherol in oxidizing soybean phosphatidylcholine liposomes; the reported apparent bimolecular rate constant was about 2 × 10^5 M^-1 s^-1 under those conditions. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C recycled the vitamin E radical back into vitamin E across this artificial membrane-water interface. organism: Glycine max lipid preparation; cell-free tissue_or_cell_type: Artificial liposomes experimental_model: Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements limitations: Membrane composition, radical initiator and assay conditions determine kinetics; no human clinical benefit or universal membrane rate is established. exposure: Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M. cross_nutrient: true evidence_location: Primary abstract radical accessibility and kinetic result [c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Guinea-pig dietary deficiency with pair feeding and precursor loading

exposure

Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.

limitations

Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Even vitamin-C-deficient animals could make substantial carnitine when given this precursor.

primary_references

[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

tissue_or_cell_type

Whole animal; urine-based synthesis estimate

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 767–778

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft

### vc-enzyme-deficient-bb-response Oral gamma-butyrobetaine increased urine-based estimated carnitine synthesis by 41–50 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even vitamin-C-deficient animals could make substantial carnitine when given this precursor. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.

experimental_model

Guinea-pig dietary deficiency with pair feeding and precursor loading

exposure

Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.

limitations

Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent.

nutrient_topic

Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

organism

Cavia porcellus

plain_language

Even vitamin-C-deficient animals could make substantial carnitine when given this precursor.

primary_references

[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

tissue_or_cell_type

Whole animal; urine-based synthesis estimate

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 754–765

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft

### vc-enzyme-deficient-tml-response Oral trimethyllysine increased urine-based estimated carnitine synthesis by 32–40 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even vitamin-C-deficient animals could make substantial carnitine when given this precursor. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5

evidence_span

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experimental_model

AREDS2 phase 3 factorial randomized trial

exposure

Lutein 10 mg + zeaxanthin 2 mg daily; background AREDS formula; median five years

limitations

Combination and background treatment prevent attribution to lutein alone; primary contrast differs from replacement and main-effects analyses. Published correction 10.1001/jama.2013.6403 changes the Table 3 lung-neoplasm row label and Table 4 lung-neoplasm entries. These records use the indexed abstract and do not reproduce the uncorrected Table 4. Correction: https://jamanetwork.com/journals/jama/fullarticle/1710434 .

nutrient_topic

Lutein research collection; topical membership is not evidence of a direct dietary effect. · Lutein

organism

4203 adults aged 50–85 at elevated AMD progression risk

plain_language

Adding the pair did not meet the primary statistical threshold.

primary_references

[lutein-p23644932] Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. (2013). https://pubmed.ncbi.nlm.nih.gov/23644932/ DOI: 10.1001/jama.2013.4997

tissue_or_cell_type

Eyes with large drusen and/or fellow-eye advanced AMD

Lutein: metabolism, signaling and nutrient connections (2026-09-17) · lines 723–734

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · AREDS2 phase 3 factorial randomized trial · source_derived_draft · unverified_draft

### lutein-areds-primary-null Primary L+Z versus placebo comparison gave HR 0.90 (98.7% CI 0.76–1.07; P=0.12). Condition category: normal nutrient_topic: Lutein research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding the pair did not meet the primary statistical threshold. organism: 4203 adults aged 50–85 at elevated AMD progression risk tissue_or_cell_type: Eyes with large drusen and/or fellow-eye advanced AMD experimental_model: AREDS2 phase 3 factorial randomized trial limitations: Combination and background treatment prevent attribution to lutein alone; primary contrast differs from replacement and main-effects analyses. Published correction 10.1001/jama.2013.6403 changes the Table 3 lung-neoplasm row label and Table 4 lung-neoplasm entries. These records use the indexed abstract and do not reproduce the uncorrected Table 4. Correction: https://jamanetwork.com/journals/jama/fullarticle/1710434 . exposure: Lutein 10 mg + zeaxanthin 2 mg daily; background AREDS formula; median five years evidence_span: {"source_cache": "artifacts/lutein-research/23644932.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1bd379926e56d7243222c2ef69d6367b74aede2b02faabfb77fadcbadf95008f", "start_char": 0, "end_char": 3037, "text_sha256": "1bd379926e56d7243222c2ef69d6367b74aede2b02faabfb77fadcbadf95008f"} [lutein-p23644932] Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. (2013). https://pubmed.ncbi.nlm.nih.gov/23644932/ DOI: 10.1001/jama.2013.4997